Project Summary The broad aim of this competitive renewal application is to shed new light on the structure and functions of the hippocampal network, with a specific emphasis on a rather mysterious and understudied neuronal cell type, the Cajal-Retzius cell (CR). The significance of studying these cells is highlighted by literature reports indicating increased densities of CRs in the hippocampus of a subpopulation of patients suffering from temporal lobe epilepsy, who also experienced febrile seizures at early ages. This observation has suggested that the physiological process controlling CR numbers and functions may be involved in the epileptogenic process. The scientific premise underlying this project relies on two main discoveries made by our laboratory. First, we have provided unequivocal evidence that hippocampal CRs are a third population of glutamatergic neurons (in addition to pyramidal and granule cells), which persist in the mature hippocampal network and are fully integrated in its microcircuits. Second, we have recently found that CRs express the polymodal, temperature-gated and Ca2+ permeable channel TRPV1. These discoveries provide unique opportunities to study the physiological and pathological functions of CRs and of the microcircuits they drive in genetically-altered animals with conditionally increased levels of TRPV1 expression or conditionally ablated vesicular glutamate transporters. In particular, we will test the hypotheses that the functional expression of TRPV1 by CRs determines their densities in the developing hippocampus and/or regulates their synaptic output. Lastly, we will test the hypothesis that temperatures in the febrile seizure range can impact hippocampal CR-dependent microcircuits via TRPV1 in vitro and in vivo.